4-amino-3-heteroaryl butyric acid compounds, compositions, and their use for treating disorders involving a dysfunction of GABAB receptors

ABSTRACT

A compound of formula (I): ##STR1## and medicinal products containing the same which are useful in treating disorders connected to a dysfunction of GABA B  receptors, are disclosed.

The present application is a division of our prior-filed copendingapplication Ser. No. 07/713,760, filed Jun. 11, 1991, now U.S. Pat. No.5,163,364 issued Nov. 10, 1992.

The invention relates to new 4-aminobutyric acid compounds.

Numerous arylpropionic compounds are known from the literature thathave, in particular, analgesic and anti-inflammatory properties. Alsoknown is baclofen or 4-amino-3-(4-chlorophenyl)butyric acid, a compoundagonistic to GABA_(B) receptors which is used in human therapeutics onaccount of its antispastic properties. Other 4-amino-3-arylbutyricacids, especially heteroarylbutyric compounds, which exhibit an affinityto the GABA_(B) receptor, have also been described (J. Med. Chem. 1987,30, 743-746).

In comparison with the compounds of the prior art, the compounds of thepresent invention exhibit a very selective and distinctly greateraffinity. In addition, some of them antagonise the excitation induced byconvulsants at doses lower than that of baclofen. Others exhibit theproperty of stimulating the synthesis of cyclic AMP in the cerebralcortex, and therefore of increasing the metabolic capacities of thebrain. The intensity of that affinity to the GABA_(B) receptor and thestrength of their activity renders possible, in human or animaltherapeutics, the administration of lower doses of the compounds of theinvention. This reduced dosage goes hand in hand with a reduction in theside effects that are observed with less active compounds since it isgenerally recognised that toxicity has no connection with the mechanismof pharmacological action but depends essentially on the chemicalstructure of the compounds. Thus, small amounts of the compounds of theinvention produce an effect comparable to that obtained with muchgreater amounts of the compounds of the prior art; the risks of toxiceffects, especially hepatic ones, are greatly reduced. That advantage isparticularly valuable in the case of the weak populations for which thecompounds are intended, generally individuals suffering from spasticdisorders or elderly individuals (Alzheimer's disease, individualssuffering from senile dementia or affected by disorders connected withsenescence), these populations often already suffering from disorders ofthe hepatic functions.

More specifically, the invention relates to new 4-aminobutyric acidcompounds corresponding to the general formula (I): ##STR2##

in which:

R₁ represents a hydroxy, amino, lower alkylamino or lower alkoxy group,or a halogen atom,

R₂ represents a hydrogen atom, a lower alkyl radical, a lower acylradical, or a lower alkoxycarbonyl radical,

R represents:

a radical of the formula ##STR3## in which:

X represents an oxygen or sulphur atom or an NH group,

Y represents a carbon, oxygen or nitrogen atom,

R'₁ and R'₂, which are identical or different, represent a halogen orhydrogen atom or a lower alkyl, lower alkoxy, hydroxy, nitro, amino,lower alkylamino or trifluoromethyl radical,

with the proviso that, when X is an oxygen atom, Y is a carbon atom andeach of R'₁ and R₂ is a hydrogen represent neither a hydrogen atom nor amethoxy group,

a radical of the formula ##STR4##

in which:

Z represents an oxygen or sulphur atom or an NH group,

T represents a carbon or nitrogen atom, R'₃ and R'₄, which are identicalor different, represent a radical selected from hydrogen, halogen, loweralkyl, lower alkoxy, hydroxy, nitro, amino, lower alkylamino ortrifluoromethyl, with the proviso that, when Z is a sulphur atom, T is acarbon atom and

R'₃ is a hydrogen atom, R'₄ may not be a methyl grouping or a hydrogen,chlorine or bromine atom, and that, when Z is an oxygen atom, T is acarbon atom and R'₃ is a hydrogen atom, R'₄ may not be a hydrogen atomor a methyl group,

a cycloalkyl radical having 4 or 5 carbon atoms or a cycloalkylalkyl ordicycloalkylalkyl radical having from 4 to 16 carbon atoms, optionallysubstituted at rings level by a group selected from halogen, hydroxy,lower alkyl, lower alkoxy, nitro, amino, lower alkylamino ortrifluoromethyl,

an optionally substituted aromatic radical having 6 ring members thatincludes 2 or 3 nitrogen atoms in its carbon skeleton,

an aromatic radical having 6 ring members that includes from 1 to 3nitrogen atoms in its carbon skeleton and is fused to a benzene ring, itbeing optionally possible for each of these 2 rings to be substituted,

or a saturated or unsaturated ring having seven ring members thatincludes one or two nitrogen atoms in its carbon skeleton and isoptionally fused to a benzene ring and is optionally substituted on thenitrogen and/or benzene ring,

the term "substituted" indicating that the groups so qualified can besubstituted by one or more groups selected from halogen atom, loweralkyl, lower alkoxy, hydroxy, trifluoromethyl, nitro, amino or loweralkylamino their optical isomers and also, where appropriate, theirsalts of addition with a pharmaceutically acceptable base or acid,

it being understood that, unless otherwise indicated, the terms "loweralkyl", "lower alkoxycarbonyl", "lower alkoxy", "lower alkylamino" and"lower acyl" indicate groups containing from 1 to 6 carbon atoms in astraight or branched chain.

Of the pharmaceutically acceptable acids or bases that can be used toconvert the compounds of the invention into salts there may bementioned, by way of non-limiting examples, hydrochloric, hydrobromic,sulphuric, nitric, oxalic, malic, maleic, succinic, tartaric,methanesulphonic, camphoric and camphosulphonic acid, sodium hydroxide,potassium hydroxide, triethylamine, diethylamine, ethanolamine ordiethanolamine, arginine, lysine, . . .

The process for the preparation of the compounds of formula (I) ischaracterised in that there is used as starting material a compound offormula (II): ##STR5##

in which R is as defined in formula (I),

which can be:

either hydrolysed by the action of a metal hydroxide to obtain, afteroptional purification, a compound of formula (I/a): ##STR6##

a particular form of the compounds of formula (I) in which R₁ representsa hydroxy group, R₂ represents a hydrogen atom and R is as defined informula (I),

or converted by the action of a lower alkyl dicarbonate in the presenceof a strong base into a compound of formula (III): ##STR7##

in which R is as defined above and R₂₃ represents a lower alkoxycarbonylgroup,

which is treated, after optional purification, with an alkali metalhydroxide in an anhydrous medium, and then with an acid to obtain acompound of formula (I/b): ##STR8##

in which R and R₂₃ are as defined above,

a particular form of the compounds of formula (I) in which R₁ representsa hydroxy group, R₂ represents a lower alkoxycarbonyl radical and R isas defined in formula (I),

which, treated in an acidic medium, yields a compound of formula (I/a)such as defined above,

which compound of formula (I/a), irrespective of the process by which ithas been obtained, may, if desired, be converted by a halogenating agentinto its halide of formula (I/c): ##STR9##

in which Hal represents a halogen atom and R is as defined in formula(I),

a particular form of the compounds of formula (I) in which R₁ representsa halogen atom, R₂ represents a hydrogen atom and R is as defined informula (I),

which compound of formula (I/a) or (I/c) can be treated, if desired:

with a compound of the formula:

    R.sub.1 "--H

in which R₁ " represents an amino, lower alkylamino or lower alkoxygroup,

to yield a compound of formula (I) in which Rl represents an amino,lower alkylamino or lower alkoxy group,

and, if desired, with an alkylating agent such as dimethyl sulphate oran alkyl halide of the formula:

    R.sub.21 --X

in which R₂₁ represents a lower alkyl group and X represents a halogenatom,

to yield a compound of formula (I) in which R₂ represents a lower alkylgroup,

or, if desired, with an acid chloride of the formula:

    R.sub.22 Cl

or an acid anhydride of the formula:

    R.sub.22 OR.sub.22

R₂₂ representing a lower acyl grouping,

to yield a compound of formula (I) in which R2 represents a lower acylgroup,

the compounds of formula (I) then, if desired, being either resolvedinto their optical isomers and then converted into salts by the additionof a pharmaceutically acceptable base or acid, or converted directlyinto salts in racemic form by the addition of a pharmaceuticallyacceptable base or acid.

The compounds of formula (II) can be obtained:

either by condensing, in an aprotic apolar solvent, an aldehyde offormula (V):

    R--CHO                                                     (V)

in which R is as defined in formula (I),

with a carboxymethylidenetriphenylphosphorane ester of formula (VI):

    (C.sub.6 H.sub.5).sub.3 --P═CH--COOR'                  (VI)

in which R' represents a lower alkyl radical,

to obtain an ester of formula (VII):

    R--CH═CH--COOR'                                        (VII)

in which R and R' are as defined above,

which is condensed in a protic polar medium with nitromethane in thepresence of a strong base, to obtain a compound of formula (VIII):##STR10##

in which R and R' are as defined above,

which is reduced in an alcoholic medium by the action of hydrogen in thepresence of a metal catalyst, to form a compound of formula (IX):##STR11##

in which R and R' are as defined above,

which is cyclised by heating to form a compound of formula (II):##STR12##

in which R is as defined in formula (I),

or by treating a compound of formula (X):

    RCOCH.sub.3                                                (X)

in which R is as defined in formula (I),

at elevated temperature and in the presence of zinc with a compound offormula (XI):

    Br--CH.sub.2 --COOA (XI)

in which A represents a lower alkyl grouping,

to yield, after optional acidic hydrolysis, extraction and purification,a compound of formula (XII): ##STR13##

in which R and A are as defined above,

which is treated with N-bromosuccinimide to yield a compound of formula(XIII): ##STR14##

in which R and A are as defined above,

which is treated with ammonia, preferably an excess thereof, to yield acompound of formula (XIV): ##STR15##

in which R is as defined above,

which is subjected to catalytic hydrogenation to obtain a compound offormula (II) as defined above.

The compounds of formula (II), wherein R does not represent:

a 2-benzofuryl group substituted in the benzene nucleus by a chlorineatom, a bromine atom or a methoxy group,

or a 2-benzothienyl group,

and the compounds of formula (III) are new and are an integral part ofthe present invention in their capacity as starting materials that canbe used for the synthesis of the compounds of the invention.

The compounds of formula (I) possess valuable pharmacologicalproperties. They have a very great and selective affinity to theGABA_(B) receptor, which is greater than that of the compounds of theprior art.

Some of them exhibit a GABA_(B) receptor-antagonising activity and cantherefore be administered in the treatment of memory disorders, mentaldisorders connected with senescence, and also in the treatment ofAlzheimer's disease.

Other compounds, on the other hand, exhibit an agonist activity and aretherefore suitable for spastic individuals or individuals suffering fromAngina pectoris.

The present invention also relates to pharmaceutical compositionscontaining the compounds of formula (I) or one of their salts ofaddition with a pharmaceutically acceptable acid or base, alone or incombination with one or more pharmaceutically acceptable inert,non-toxic excipients or carriers.

Of the pharmaceutical compositions according to the invention there maybe mentioned more particularly those that are suitable for oral,parenteral, nasal, rectal, perlingual, ocular or pulmonaryadministration, and especially injectable preparations, aerosols, eye ornose drops, tablets or dragees, sublingual tablets, soft gelatincapsules, sachets, suppositories, creams, ointments, dermal gels, . . .

The dosage varies according to the age and weight of the patient, theroute of administration, the nature of the disorder and any associatedtreatment and ranges from 1 mg to 1 gram per 24 hours.

The following Examples illustrate the invention and do not limit it inany way.

The starting materials are described in the literature or can beprepared in a similar manner.

The 1H nuclear magnetic resonance spectra (NMR) were produced usingtetramethylsilane (TMS) as the internal reference. The chemicaldisplacements are expressed in parts per million (ppm).

The infrared spectra were effected in the form of potassium bromidediscs containing approximately 1% of the product to be analysed.

EXAMPLE 1 3 (2-(5 isopropylbenzofur 1)) 4 aminobutanoic acid

STAGE A : ethyl 3-(2-(5-isopropylbenzofuryl))propenoate

A solution containing 0.1 mol of 2-(5-isopropyl)benzofurylcarbaldehydeand 0.1 mol of ethoxycarbonylmethylidenetriphenylphosphorane in 200 cm³of benzene is heated under reflux for 4 hours under a nitrogenatmosphere. It is then cooled and the solvent is evaporated underreduced pressure. The residue is taken up in 200 cm³ of ether, theinsoluble material is removed by suction-filtering and the filtrate isevaporated to dryness and then the evaporation residue is distilledunder reduced pressure. The compound of stage A is obtained:

b.p. (3 mm Hg)=186° C.

STAGE B : ethyl 3-(2-(5-isopropylbenzofuryl))-4-nitrobutanoate

0.05 mol of the compound obtained in stage A of Example 1 is heated for18 hours at 70° C. in 50 cm³ of nitromethane and 2 cm³ of a 40%methanolic solution of Triton B. The whole is cooled, neutralised with amolar solution of hydrochloric acid and extracted with ether. Theethereal phase is washed with water, dried, filtered and then evaporatedto dryness. The compound of stage B is obtained after purification byhigh performance liquid chromatography.

STAGE C : 4-(2-(5-isopropylbenzofuryl))-2-oxopyrrolidine

0.05 mol of the compound obtained in stage B of Example 1 is reduced inan ethanolic solution by hydrogen at atmospheric pressure and at ambienttemperature in the presence of Raney nickel. The whole is filtered andevaporated under reduced pressure, and then the residue is heated for 2hours and recrystallised from petroleum ether.

Melting point: 151° C.

Spectral characteristics:

infrared: 1690 cm⁻¹ : νCO; 3300 m⁻¹ : νNH;

NMR (CDCl₃): δ:1.26 ppm:doublet:((CH₃)₂ C); δ:2.75 ppm:doublet:(CH₂ CO);δ:2.80-3.20 ppm:multiplet:(CH (CH₃)₂); δ:3.40-4.10 ppm:multiplet:(CH,CH₂ N); δ:5.70 ppm:singlet:(NH); δ:6.50 ppm:singlet:(H₃ ', benzofuran);δ:7.00-7.50 ppm:multiplet:(H₄ ', H₆ ', H₇ '; benzofuran),

STAGE D : 3-(2-(5-isopropylbenzofuryl))-4-aminobutanoic acid

0.01 mol of the compound obtained in stage C of Example 1 is heatedunder reflux for one hour in 20 cm³ of 95% ethanol in the presence of 5cm³ of 40% sodium hydroxide solution. The whole is cooled and evaporatedto dryness. The residue is taken up in from 15 to 20 cm³ of water thathas been acidified to pH=1 by 10% HCl. The whole is evaporated todryness, taken up in from 1 to 3 cm³ of trifluoroacetic acid andchromatographed over an ion exchange resin (DOWEX 50 WH+) using a 5%ammonium hydroxide solution as eluant. The eluant is evaporated todryness and the residue is recrystallised from ethanol.

Melting point: 190° C.

Spectral characteristics:

infrared: 1580 cm⁻ : νCO; 2300-3200 cm⁻¹ : νOH;

EXAMPLE 2: 3 (2 (5 methylbenzofuryl))-4-aminobutanoic acid

By following the instructions in stages A to D of Example 1, butreplacing the 2-(5-isopropyl)benzofurylcarbaldehyde in stage A ofExample 1 by 2-(5-methyl)benzofurylcarbaldehyde, there are obtained insuccession, after a purification stage by high performance liquidchromatography, as appropriate, the following compounds:

STAGE A : ethyl 3-(2-(5-methylbenzofuryl))propenoate

Melting point: 73° C.

STAGE B : ethyl 3-(2-(5-methylbenzofuryl))-4-nitrobutanoate

STAGE C : 4-(2-(5-methylbenzofuryl))-2-oxopyrrolidine

Melting point: 151° C.

Spectral characteristics:

infrared: 1690 cm⁻ : νCO; 3300 m⁻¹ : νNH;

NMR (CDCl₃): δ: 2.41 ppm:singlet:(CH₃); δ: 2.69 ppm:doublet:(CH₂ CO); δ:3.50-4.10 ppm:multiplet:(CH₂ N, CH); δ: 6.00 ppm:singlet:(NH); δ: 6.46ppm:singlet:(H₃ ', benzofuran); δ: 6.90-7.50 ppm:multiplet:(H₄ ', H₆ ',H₇ '; benzofuran);

STAGE D : 3-(2-(5-methylbenzofuryl))-4-aminobutanoic acid

Meltinq point: 191° C.

Spectral characteristics:

infrared: 1580 cm⁻¹ : νCO; 2300-3200 cm--¹ : ν(COO--, NH₃ +);

EXAMPLE 3 3-(2 (5-ethylbenzofuryl)) 4 aminobutanoic acid

By following the instructions in stages A to D of Example 1, butreplacing the 2-(5-isopropyl)benzofurylcarbaldehyde in stage A ofExample 1 by 2-(5-ethyl)benzofurylcarbaldehyde, there are obtained insuccession, after a purification stage by high performance liquidchromatography, as appropriate, the following compounds:

STAGE A : ethyl 3-(2-(5-ethylbenzofuryl))propenoate

Melting point: 52° C.

STAGE B : ethyl 3-(2-(5-ethylbenzofuryl))-4-nitrobutanoate

STAGE C : 4-(2-(5-ethylbenzofuryl))-2-oxopyrrolidine

Melting point: 125°-127° C.

Spectral characteristics:

infrared: 1670 cm⁻¹ : νCO; 3200 m⁻¹ : νNH.

NMR (CDCl₃): δ:1.25 ppm:triplet:(CH₂ --CH₃); δ:2.50-3.00ppm:multiplet:(CH₂ --CH₃, CH₂ CO); δ:3.40-4.10 ppm:multiplet:(CH₂ N,CH); δ:5.93 ppm:singlet:(NH); δ:6.46 ppm:singlet:(H₃ ', benzofuran);δ:7.00-8.00 ppm:multiplet:(H₄ ', H₆ ', H₇ '; benzofuran).

STAGE D : 3-(2-(5-ethylbenzofuryl))-4-aminobutanoic acid

Melting point: 195° C.

Spectral characteristics:

infrared: 1580 cm⁻¹ : νCO. 3200 cm⁻¹ : νOH.

EXAMPLE 4: 3-(2-(5 (1-methylpropyl)benzofuryl))-4-aminobutanoic acid

By following the instructions in stages A to D of Example 1, butreplacing the 2-(5-isopropyl)benzofurylcarbaldehyde in stage A ofExample 1 by 2-(5-(1-methylpropyl))benzofurylcarbaldehyde, there areobtained in succession, after a purification stage by high performanceliquid chromatography, as appropriate, the following compounds:

STAGE A : ethyl 3-(2-(5-(1-methylpropyl)benzofuryl))propenoate

b.p. (0.5 mm Hg)=165° C.

STAGE B : ethyl 3-(2-(5-(1-methylpropyl)benzofuryl))-4-nitrobutanoate

STAGE C : 4-(2-(5-(1-methylpropyl)benzofuryl))-2-oxopyrrolidine

Melting point: 111°-113° C.

Spectral characteristics:

infrared: 1700 cm⁻¹ : νCO; 3200 m⁻¹ : νNH.

NMR (CDCl₃): δ:0.80 ppm:triplet:(CH₃ --CH₂ --); δ:1.28 ppm:doublet:(CH₃--CH--); δ:1.45--1.80 ppm:multiplet:(--CH₂ --CH); δ:2.68ppm:doublet:(CH₂ CO); δ:3.50-4.10 ppm:multiplet:(CH₂ N, CH) δ:5.66ppm:singlet:(NH); δ:6.49 ppm:singlet:(H₃ ', benzofuran) . δ:7.00-7.50ppm:multiplet:(H₄ ', H₆ ', H₇ '; benzofuran).

STAGE D : 3-(2-(5-(1-methylpropyl)benzofuryl))-4-aminobutanoic acid

Melting point: 200° C.

Spectral characteristics:

infrared: 1580 cm⁻¹ : νCO; 2300-3200 cm⁻¹ : νOH;

EXAMPLE 5 3-(2-(5-fluorobenzofuryl))-4-aminobutanoic acid

By following the instructions in stages A to D of Example 1, butreplacing the 2-(5-isopropyl)benzofurylcarbaldehyde in stage A ofExample 1 by 2-(5-fluoro)benzofurylcarbaldehyde, there are obtained insuccession, after a purification stage by high performance liquidchromatography, as appropriate, the following compounds:

STAGE A : ethyl 3-(2-(5-fluorobenzofuryl))propenoate

Melting point: 112° C.

STAGE B : ethyl 3-(2-(5-fluorobenzofuryl))-4-nitrobutanoate

STAGE C : 4-(2-(5-fluorobenzofuryl))-2-oxopyrrolidine

Melting point: 178°-180° C.

Spectral characteristics:

infrared: 1690 cm⁻¹ : νCO; 3200 m⁻¹ : νNH.

NMR (CDCl₃): δ:2.70 ppm:doublet:(CH₂ CO); δ:3.40-4.10 ppm:multiplet:(CH₂N, CH); δ:5.75 ppm:singlet:(NH); δ:6.50 ppm:singlet:(H₃ '; benzofuran);δ:6.80-7.50 ppm:multiplet:(H₄ ', H₆ ', H₇ '; benzofuran).

STAGE D : 3-(2-(5-fluorobenzofuryl))-4-aminobutanoic acid

Melting point: 200°-202° C.

Spectral characteristics:

infrared: 1580 cm⁻¹ : νCO; 2300-3200 cm⁻¹ : νOH.

NMR (D₂ O): δ:2.76 ppm:doublet:(CH₂ CO); δ:3.30-4.00 ppm:multiplet:(CH₂N, CH); δ:6.88 ppm:singlet:(H₃ '; benzofuran); δ:6.90-7.90ppm:multiplet:(H₄ ', H₆ ', H₇ '; benzofuran).

EXAMPLE 6 3 (2-(5-bromobenzofuryl)) 4-aminobutanoic acid

By following the instructions in stages A to D of Example 1, butreplacing the 2-(5-isopropyl)benzofurylcarbaldehyde in stage A ofExample 1 by 2-(5-bromo)benofurylcarbaldehyde, there are obtained insuccession, after a purification stage by high performance liquidchromatography, as appropriate, the following compounds:

STAGE A : ethyl 3-(2-(5-bromobenzofuryl))propenoate

STAGE B : ethyl 3-(2-(5-bromobenzofuryl))-4-nitrobutanoate

STAGE C : 4-(2-(5-bromobenzofuryl))-2-oxopyrrolidine

STAGE D : 3-(2-(5-bromobenzofuryl))-4-aminobutanoic acid

Melting point: 200°-202° C.

Spectral characteristics:

infrared 1580 cm⁻¹ : νCO; 2300-3200 cm⁻¹ : νOH.

NMR (D₂ O) : δ:2.76 ppm:doublet:(CH₂ CO); δ:3.30-4.00 ppm:multiplet:(CH₂N, CH) δ:6.88 ppm:singlet:Ch₃ '; benzofuran); δ:6.90-7.90ppm:multiplet:(H₄ ', H₆ ', H₇ '; benzofuran).

EXAMPLE 7 3 (2-(4,5-dichlorothienyl))-4-aminobutanoic acid

By following the instructions in stages A to D of Example 1, butreplacing the 2-(5-isopropyl)benzofurylcarbaldehyde in stage A ofExample 1 by 2-(4,5-dichloro)thienylcarbaldehyde, there are obtained insuccession, after a purification stage by high performance liquidchromatography, as appropriate, the following compounds:

STAGE A : ethyl 3-(2-(4,5-dichlorothienyl))propenoate

Melting point: 76°-78° C.

STAGE B : ethyl 3-(2-(4,5-dichlorothienyl))-4-nitrobutanoate

STAGE C : 4-(2-(4,5-dichlorothienyl))-2-oxopyrrolidine

STAGE D : 3-(2-(4,5-dichlorothienyl))-4-aminobutanoic acid

Melting point: 188°-195° C.

Spectral characteristics:

infrared 2500-3400 cm⁻¹ : wide band (NH₃ +,COO--) 1590 cm⁻¹ : νCO.

NMR (D₂ O): δ:2.6 ppm:doublet:(CH₂ CO); δ:3.1-3.5 ppm:multiplet:##STR16## δ:7 ppm:singlet:(H:thiophene).

EXAMPLE 8 3 (2-imidazolyl)-4-aminobutanoic acid

By following the instructions in stages A to D of Example 1, butreplacing the 2-(5-isopropyl)benzofurylcarbaldehyde in stage A ofExample 1 by 2-imidazolylcarbaldehyde, there are obtained in succession,after a purification stage by high performance liquid chromatography, asappropriate, the following compounds:

STAGE A : ethyl 3-(2-imidazolyl)propenoate

STAGE B : ethyl 3-(2-imidazolyl)-4-nitrobutanoate

STAGE C : 4-(2-imidazolyl)-2-oxopyrrolidine

Spectral characteristics:

infrared:3200-3100 cm⁻¹ : νNH; 1700 cm⁻¹ : νCO. δ:2.5 ppm:doublet:(CH₂CO); δ:3.5 ppm:multiplet: ##STR17## δ:6.9 ppm:singlet:(H₂ '; imidazole);δ:7.5 ppm:singlet:(NH--CO); δ:10-11 ppm:singlet:(NH ; imidazole).

STAGE D: 3-(2-imidazolyl)-4-aminobutanoic acid

Melting point: 175°-180° C.

Spectral characteristics:

infrared 2700-3400 cm⁻¹ : ν(COO--, NH₃ +); 1590 cm⁻¹ : νCO.

NMR (D₂ O): δ:2.6 ppm:doublet:(CH₂ CO); δ:3.2-3.7 ppm:multiplet:(CH--CH₂--NH); δ:7.05 ppm:singlet:(H₂ '; imidazole).

EXAMPLE 9 3-(2-(5-chlorobenzofuryl)) 4-aminobutanoic acid

By following the instructions in stages A to C of Example 1, butreplacing the 2-(5-isopropyl)benzofurylcarbaldehyde in stage A ofExample 1 by 2-(5-chloro)benzofurylcarbaldehyde, the following compoundsare obtained in succession:

STAGE A : ethyl 3-(2-(5-chlorobenzofuryl))propenoate

STAGE B : ethyl 3-(2-(5-chlorobenzofuryl))-4-nitrobutanoate

STAGE C : 4-(2-(5-chlorobenzofuryl))-2-oxopyrrolidine

STAGE D :1-tert.-butoxycarbonyl-2-oxo-4-(2-(5-chlorobenzofuryl))pyrrolidine

0.01 mol of triethylamine, 0.02 mol of di-tert.-butyl dicarbonate and0.01 mol of dimethylaminopyridine are added under a nitrogen atmosphereand at ambient temperature to 0.01 mol of the compound obtained in stageC of Example 9 in solution in 50 cm³ of methylene chloride. The reactionmixture is stirred for 7 hours and then evaporated to dryness. Theresidue obtained is taken up in 25 cm³ of ether and the precipitateformed is removed by filtration. The ethereal phase is washed withwater, dried and recrystallised from diisopropyl ether.

Melting point : 123° C.

Spectral characteristics:

infrared 3100 cm⁻¹ : νNH; 1800 cm⁻¹ : νCO (tert.-butoxycarbonyl); 1690cm⁻¹ : νCO (lactam).

NMR (CDCl₃): δ:1.5 ppm:singlet:(tert.-butoxycarbonyl); δ:2.9ppm:doublet:(CH₂ --CO), δ:4 ppm:multiplet:(CH--CH₂ --N); δ:6.5ppm:singlet:(H₃ '; benzofuran); δ:7.15 ppm:doublet:(H₆ '; benzofuran);δ:7.25 ppm:doublet:(H₇ '; benzofuran); δ:7.5 ppm:doublet:(H₄ ';benzofuran).

STAGE E : 4-tert.-butoxycarbonylamino-3-(2-(5-chlorobenzofuryl))butanoicacid

0.01 mol of a molar solution of lithium hydroxide is added at ambienttemperature to 0.01 mol of the compound obtained in stage D of Example 9in solution in tetrahydrofuran. The reaction mixture is stirred forthirty minutes, the solvent is evaporated, the residue is taken up in 25cm³ of water and then acidified with a 10% acetic acid solution. Thewhole is extracted with ether, dried, filtered, evaporated andrecrystallised from hexane.

M.p.° C.: 104° C.

STAGE F : 3-(2-(5-chlorobenzofuryl))-4-aminobutanoic acid

A mixture of 0.005 mol of the compound obtained in stage E of Example 9and 0.25 mol of trifluoroacetic acid in 100 cm³ of dichloromethane isstirred for one hour at ambient temperature and then evaporated todryness. The residue is taken up in 25 cm³ of water and then acidifiedto pH=1 with a solution of 10% hydrochloric acid, taken up in from 1 to3 cm³ of trifluoroacetic acid, and chromatographed on an ion exchangeresin (DOWEX 50 WH+) using a 5% ammonium hydroxide solution as eluant.The eluant is evaporated to dryness and the residue is recrystallisedfrom water.

M.p.° C.: 190°-192° C. 3300 cm⁻¹ : ν(COO--, NH₃ +); cm⁻¹ : νCO.

NMR (D₂ O): δ:2.75 ppm:doublet, 2H:(CH₂ --COOH); δ:3.25-4ppm:multiplet--3H:(CH--CH₂ --NH₂); δ:6.8 ppm:singlet--1H:(furan);δ:7.25-7.75 ppm:multiplet--3H : (benzene).

EXAMPLE 10 3 (2-benzothienyl) 4-aminobutanoic acid

By proceeding as in Example 9, but initially using2-benzothienylcarbaldehyde in stage A of Example 9, there are obtained:

STAGE D : 1-tert.-butoxycarbonyl-2-oxo-4-(2-benzothienyl)pyrrolidine

and in STAGE F : the title product:

M.p.° C.:192°-197° C. 3200 cm⁻¹ : ν(COO--, NH₃ +); 1575 cm⁻¹ : νCO.

NMR (D₂ O): δ:2.7 ppm:doublet--2H : (CH₂ --CO); δ:3.3-3.5ppm:multiplet--2H:(CH₂ --NH₂); δ:3.75 ppm:multiplet--1H:(CH);δ:7.25-8.10 ppm:multiplet--5H : (benzothiophene).

EXAMPLE 11 3 (2 (5 ethoxybenzofuryl))-4 aminobutanoic acid

By proceeding as in Example 9, but initially using2-(5-ethoxy)benzofurylcarbaldehyde in stage A of Example 9, there areobtained:

STAGE C : 4-(2-(5-ethoxybenzofuryl)-2-oxopyrrolidine

Melting point: 146°-148° C.

Spectral characteristics:

infrared: 1675 cm⁻¹ : νCO;

NMR (CDCl₃): 3250 cm⁻¹ : νNH. δ:1.35 ppm:triplet:(O--CH₂ --CH₃);δ:2.50-2.70 ppm:doublet:(CH₂, CO); δ:3.50-4.10 ppm:multiplet:(CH₂ N, CH,O--CH₂ --CH₃); δ:6.15 ppm:singlet:(NH); δ:6.47 ppm:singlet:(H₃ ';benzofuran); δ:6.85 ppm:doublet:(H₄ '; benzofuran); δ:7.00ppm:doublet:(H₆ '; benzofuran); δ:7.30 ppm:doublet:(H₇ '; benzofuran).

STAGE D :1-tert.-butoxycarbonyl-2-oxo-4-(2-(5-ethoxybenzofuryl))pyrrolidine

and in STAGE F : the title product:

Melting point: 200° C.

Spectral characteristics:

infrared: 2300-3200 cm⁻¹ : ν(COO--, NH₃ +); 1620 cm⁻¹ : νCO.

NMR (D₂ O):

δ:1.40 ppm:triplet:(CH₃); δ:2.60:doublet:(CH₂ CO); δ:3.30-3.95ppm:multiplet:(CHp13 CH₂ --NH₂); δ:4.10 ppm:quintuplet:(OCH₂); δ:6.75ppm:singlet:(H₃ '; benzofuran); δ:7.00 ppm:doublet:(H₆ '; benzofuran);δ:7.20 ppm:doublet:(H₄ '; benzofuran).

EXAMPLE 12 3-(2-benzothiazolyl)-4-aminobutanoic acid

By proceeding as in Example 9, but initially using2-benzothiazolylcarbaldehyde in stage A of Example 9, there areobtained:

STAGE C : 4-(2-benzothiazolyl)-2-oxopyrrolidine

STAGE D : 1-tert.-butoxycarbonyl-2-oxo-4-(2-benzothiazolyl)pyrrolidine

and in STAGE F : the title product.

EXAMPLE 13 3-(2 (5 trifluoromethylbenzofuryl))-4-aminobutanoic acid

By proceeding as in Example 9, but initially using2-(5-trifluoromethyl)benzofurylcarbaldehyde in stage A of Example 9,there are obtained:

STAGE C : 4-(2-(5-trifluoromethylbenzofuryl))-2-oxopyrrolidine

STAGE D :1-tert.-butoxycarbonyl-2-oxo-4-(2-(5-trifluoromethylbenzofuryl))pyrrolidine

and in STAGE F : the title product.

EXAMPLE 14: 3-(2-(4-trifluoromethylthienyl)) 4-aminobutanoic acid

By proceeding as in Example 9, but initially using2-(4-trifluoromethyl)thienylcarbaldehyde in stage A of Example 9, thereare obtained:

STAGE C : 4-(2-(4-trifluoromethylthienyl))-2-oxopyrrolidine

STAGE D :1-tert.-butoxycarbonyl-2-oxo-4-(2-(5-trifluoromethylthienyl))pyrrolidine

and in STAGE F : the title product.

EXAMPLE 15 3-dicyclopropylmethyl-4 aminobutanoic acid

By proceeding as in Example 9, but initially using2-dicyclopropylmethylcarbaldehyde in stage A of Example 9, there areobtained:

STAGE C : 4-dicyclopropylmethyl-2-oxopyrrolidine

STAGE D : 1-tert.-butoxycarbonyl-2-oxo-4-dicyclopropylmethylpyrrolidine

and in STAGE F : the title product.

EXAMPLE 16 3-(2-imidazolyl) 4-aminobutanoic acid methyl ester

STAGE A : 3-(2-imidazolyl)-4-aminobutanoic acid chloride

0.01 mol of 3-(2-imidazolyl)-4-aminobutyric acid chloride is dissolvedin 30 cm3 of methylene chloride. 0.025 mol of thionyl chloride is addedand the whole is stirred at ambient temperature for 2 hours. Thereaction medium is evaporated and the residue is extracted twice withchloroform after being rendered alkaline. The chloroform phases arecombined and dried over calcium chloride and the chloroform isevaporated off. The residue is recrystallised.

STAGE B : 3-(2-imidazolyl)-4-aminobutanoic acid methyl ester

0.01 mol of the compound obtained in stage A of Example 16 is dissolvedin 30 cm³ of pyridine. 1 cm³ of methanol is added. The whole is heatedunder reflux for five hours, the reaction medium is evaporated in vacuoon a water bath. The residue is dried and purified by chromatography.

EXAMPLE 17 3-(2-imidazolyl) 4-aminobutyramide

0.01 mol of the 3-(2-imidazolyl)-4-aminobutanoic acid chloride obtainedin Example 12, stage A, is dissolved in 50 cm³ of chloroform. A currentof ammonia is bubbled in over a period of 2 hours. The reaction mediumis evaporated to dryness and the residue is recrystallised.

EXAMPLE 18 3-(2 imidazolyl)-4-amino-N-propylbutyramide

0.01 mol of the compound obtained in stage A of Example 16 is dissolvedin 50 cm³ of chloroform. 0.025 mol of propylamine is added and the wholeis heated under reflux for 5 hours while stirring and then cooled. Thereaction mixture is then evaporated to dryness and extracted twice withchloroform. The chloroform phases are combined and dried over calciumchloride and the solvent is evaporated in vacuo on a water bath. Theresidue is purified by chromatography.

EXAMPLE 19 3-(2 (5-isopropylbenzofuryl)) 4-aminobutanoic acid methylester

By proceeding as in Example 16, but replacing the3-(2-imidazolyl)-4-aminobutyric acid in stage A of Example 16 by3-(2-(5-isopropylbenzofuryl))-4-aminobutyric acid, the title compound isobtained.

EXAMPLE 20 3(2-(5-isopropylbenzofuryl))-4-methylaminobutanoic acid methyester

0.01 mol of the compound of Example 19 is dissolved in 100 cm³ ofchloroform. 0.011 mol of dimethyl sulphate is added dropwise. The wholeis stirred for 3 hours and the organic phase is washed with water anddried. The organic phase is evaporated to dryness and the residue ispurified by chromatography.

EXAMPLE 21 3-cyclopropylmethyl-4 aminobutanoic acid

By proceeding as in Example 1, but replacing the2-(5-isopropyl)benzofurylcarbaldehyde in stage A of Example 1 bycyclopropylacetaldehyde, there are obtained:

in STAGE C : 4-cyclopropylmethyl-2-oxopyrrolidine,

and in STAGE D : the title compound.

EXAMPLE 22 3-(2-(4,5-dichloroimidazolyl)) 4 aminobutanoic acid

By proceeding as in Example 1, but replacing the2-(5-isopropyl)benzofurylcarbaldehyde in stage A of Example 1 by2-(4,5-dichloro)imidazolylcarbaldehyde there are obtained:

in STAGE C : 4-(2-(4,5-dichloroimidazolyl))-2-oxopyrrolidine,

and in STAGE D : the title compound.

EXAMPLE 23 3-(2-(4-methylimidazolyl))-4-aminobutanoic acid

By proceeding as in Example 1, but replacing the2-(5-isopropyl)benzofurylcarbaldehyde in stage A of Example 1 by2-(4-methyl)imidazolylcarbaldehyde there are obtained:

in STAGE C : 4-(2-(4-methylimidazolyl))-2-oxopyrrolidine,

and in STAGE D : the title compound.

EXAMPLE 24 3-(2-(4,5-dichlorofuryl))-4-aminobutanoic acid

By proceeding as in Example 1, but replacing the2-(5-isopropyl)benzofurylcarbaldehyde in stage A of Example 1 by2-(4,5-dichloro)furylcarbaldehyde, there are obtained:

in STAGE C : 4-(2-(4,5-dichlorofuryl))-2-oxopyrrolidine,

and in STAGE D : the title compound.

EXAMPLE 25 3-(2-(4-methoxybenzothienyl))-4-aminobutanoic acid

By proceeding as in Example 9, but using initially in stage A of Example9 2-(4-methoxy)benzothienylcarbaldehyde, there are obtained:

in STAGE C : 4-(2-(4-methoxybenzothienyl))-2-oxopyrrolidine,

in STAGE D :1-tert.-butoxycarbonyl-2-oxo-4-(2-(4-methoxybenzothienyl))pyrrolidine,

and in STAGE F : the title compound.

EXAMPLE 26 3-(2-imidazolyl)-4 acetylaminobutanoic acid methyl ester

0.01 mol of the compound obtained in stage B of Example 16 is dissolvedin 50 cm3 of chloroform. 0.01 mol of acetic anhydride and 0.015 mol ofsodium carbonate are added. The whole is heated under reflux for fivehours while stirring. The reaction mixture is then cooled, evaporated todryness and extracted with chloroform twice. The chloroform phases arecombined and dried over calcium chloride and the solvent is evaporatedin vacuo on a water bath. The residue is purified by chromatography.

EXAMPLE 27 3-(2-(4 methoxyfuryl))-4 aminobutanoic acid

By proceeding as in Example 1, but using 2-(4-methoxy)furylcarbaldehydein stage A of Example 1 instead of2-(5-isopropyl)benzofurylcarbaldehyde, there are obtained:

in STAGE C : 4-(2-(4-methoxyfuryl))-2-oxopyrrolidine,

and in STAGE D : the title compound.

EXAMPLE 28 3-(4-pyridazinyl)-4-aminobutanoic acid

By proceeding as in Example 1, but using 4-pyridazinylcarbaldehyde instage A of Example 1 instead of 2-(5-isopropyl)benzofurylcarbaldehyde,there are obtained:

in STAGE C : 4-(4-pyridazinyl)-2-oxopyrrolidine,

and in STAGE D : the title compound.

EXAMPLE 29 3-(2-pyrimidinyl)-4-aminobutanoic acid

By proceeding as in Example 1, but using 2-pyrimidinylcarbaldehyde instage A of Example 1 instead of 2-(5-isopropyl)benzofurylcarbaldehyde,there are obtained:

in STAGE C :4-(2-pyrimidinyl)-2-oxopyrrolidine,

and in STAGE D : the title compound.

EXAMPLE 30: 3 (2-benzimidazolyl)-4-aminobutanoic acid

By proceeding as in Example 1, but using 2-benzimidazolylcarbaldehyde instage A of Example 1 instead of 2-(5-isopropyl)benzofurylcarbaldehyde,there are obtained:

in STAGE C : 2-(2-benzimidazolyl)-2-oxopyrrolidine,

and in STAGE D : the title compound.

EXAMPLE 31 3-(3-azepinyl) 4 aminobutanoic acid

By proceeding as in Example 1, but using 3-azepinylcarboxaldehyde instage A of Example 1 instead of 2-(5-isopropyl)benzofurylcarbaldehyde,there are obtained:

in STAGE C : 4-(3-azepinyl)-2-oxopyrrolidine,

and in STAGE D : the title compound.

EXAMPLE 32 3-(3-(1,4 diazepinyl))-4-aminobutanoic acid

By proceeding as in Example 1, but using(3-(1,4-diazepinyl))carboxaldehyde in stage A of Example 1 instead of2-(5-isopropyl)benzofurylcarbaldehyde, there are obtained:

in STAGE C : 4-(3-(1,4-diazepinyl))-2-oxopyrrolidine,

and in STAGE D : the title compound.

EXAMPLE 33 3-(3 benzo[b]azepinyl)-4 aminobutanoic acid

By proceeding as in Example 1, but using (3-benzo[b]azepinylcarbaldehydein stage A of Example 1 instead of2-(5-isopropyl)benzofurylcarbaldehyde, there are obtained:

in STAGE C : 4-(3-benzo[b]azepinyl)-2-oxopyrrolidine,

and in STAGE D : the title compound.

EXAMPLE 34 3-(2 (1,3,5 triazinyl)) 4-aminobutanoic acid

By proceeding as in Example 1, but using(2-(1,3,5-triazinyl))carbaldehyde in stage A of Example 1 instead of2-(5-isopropyl)benzofurylcarbaldehyde, there are obtained:

in STAGE C : 4-(2-(1,3,5-triazinyl))-2-oxopyrrolidine,

and in STAGE D : the title compound.

EXAMPLE 35 3-(2-indolyl)-4-aminobutanoic acid

By proceeding as in Example 9, but using initially in stage A of Example9 2-indolylcarbaldehyde, there are obtained:

STAGE C : 4-(2-indolyl)-2-oxopyrrolidine,

STAGE D : 1-tert.-butoxycarbonyl-2-oxo-4-(2-indolyl)pyrrolidine,

and in STAGE F : the title compound.

EXAMPLE 36 3 (2-(5 methoxyindolyl))-4-aminobutanoic acid

By proceeding as in Example 9, but using initially in stage A of Example9 2-(5-methoxy)indolylcarbaldehyde, there are obtained:

STAGE C : 4-(2-(5-methoxyindolyl))-2-oxopyrrolidine,

STAGE D :1-tert.-butoxycarbonyl-2-oxo-4-(2-(5-methoxyindolyl))pyrrolidine,

and in STAGE F : the title compound.

EXAMPLE 37 3-(2-(5-methylindolyl))-4-aminobutanoic acid

By proceeding as in Example 9, but using initially in stage A of Example9 2-(5-methyl)indolylcarbaldehyde, there are obtained:

STAGE C : 4-(2-(5-methylindolyl))-2-oxopyrrolidine,

STAGE D : 1-tert.-butoxycarbonyl-2-oxo-4-(2-(5-methylindolyl))pyrrolidine,

and in STAGE F : the title compound.

EXAMPLE 38 3-(2 (5-chloroindolyl))-4 aminobutanoic acid

By proceeding as in Example 9, but using initially in stage A of Example9 2-(5-chloro)indolylcarbaldehyde, there are obtained:

STAGE C : 4-(2-(5-chloroindolyl))-2-oxopyrrolidine,

STAGE D :1-tert.-butoxycarbonyl-2-oxo-4-(3-(5-chloroindolyl))pyrrolidine,

and in STAGE F: the title compound.

EXAMPLE 394-tert.-butoxycarbonylamino-3-(2-(5-methoxybenzofuryl))butanoic acid

By proceeding as in Example 9, but initially using2-(5-methoxy)benzofurylcarbaldehyde in Stage A of Example 9, there isobtained:

in STAGE D :1-tert.-butoxycarbonyl-2-oxo-4-(2-(5-methoxybenzofuryl))pyrrolidine

Melting point:90°-92° C.

Spectral characteristics:

infrared 1710-1740 cm⁻¹ : νCO;

NMR (CDCl₃) : δ:1.53 ppm:singlet:(C(CH₃)₃); δ:2.87 ppm:doublet:(CH₂ CO);δ:3.83 ppm:multiplet:(CH₃ O, CH, CH₂ N); δ:6.48 ppm:singlet:(H₃ ';benzofuran); δ:6.87 ppm:doublet:(H₆ '; benzofuran); δ:7.00ppm:doublet:(H₄ '; benzofuran); δ:7.44 ppm:doublet:(H₇ '; benzofuran).

and in STAGE E: the title product:

Melting point:149°-153° C.

Spectral characteristics:

infrared : 1700-1720 cm⁻¹ : νCO; 3420 cm⁻¹ : νNH.

NMR (CDCl₃): δ:1.40 ppm:singlet:(C(CH₃)₃); δ:2.70-2.90ppm:multiplet:(CH₂ CO); δ:3.40-3.70 ppm:multiplet:(CH₂ N, CH);δ:3.82ppm:singlet:(CH₃ O); δ:4.70ppm:singlet:(NH); δ:6.45ppm:singlet:(H₃ '; benzofuran); δ:6.82 ppm:doublet:(H₆ '; benzofuran);δ:6.95 ppm:doublet:(H₄ '; benzofuran); δ:7.33 ppm:doublet:(H₇ ';benzofuran).

EXAMPLE 40: 4tert.-butoxycarbonylamino-3-(2-(5-methoxybenzofuryl))butanamide

STAGE A :4-tert.-butoxycarbonylamino-3-(2-(5-methoxybenzofuryl))butanamide acidchloride

By proceeding as in stage A of Example 16, but replacing the3-(2-imidazolyl)-4-aminobutyric acid by the compound of Example 39, theproduct of stage A is obtained.

STAGE B :4-tert.-butoxycarbonylamino-3-(2-(5-methoxybenzofuryl))butanamide

By proceeding as in Example 17, but replacing the3-(2-imidazolyl)-4-aminobutanoic acid chloride by the compound obtainedin stage A of Example 40, the title product is obtained:

Melting point:175°-177° C.

Spectral characteristics:

infrared : 1665-1700 cm⁻¹ : νCO; 3400 cm⁻¹ : νNH.

Pharmacological Study of the Compounds of the Invention

EXAMPLE 41 Acute Toxicity Study

Acute toxicity was assessed after the oral administration to groups of 5mice (20 +2 grams) of increasing doses (0.05; 0.1; 0.25; 0.50; 0.75g/kg). The animals were observed at regular intervals over the course ofthe first day and daily for the two weeks following treatment.

It appears that the compounds of the invention are atoxic.

EXAMPLE 42 Study of the Affinity to GABA_(B) Receptors

This study was carried out in accordance with conventional binding studytechniques.

It appears that the compounds of the invention have a very strongaffinity to GABA_(B) receptors.

Thus, some of the compounds of the invention have an IC₅₀ of 0.05 μM inthe presence of R(-) [³ H] baclofen. By way of comparison, the bestcompound of the prior art having a similar structure (J. Med. Chem.1987, 30, 743-746) had an IC₅₀ in this test of 0.61 μM and baclofen hadan IC₅₀ of 0.33 μM.

EXAMPLE 43 Study of the Inhibition of Excitation Activity Induced byConvulsants

The compounds of the invention antagonise the excitatory activityinduced by convulsants in hippocampal o preparations.

Hippocampal preparations were prepared from the brains of sacrificedadult female rats. Transverse sections were placed in a preservativemedium. After 1 hour and 30 minutes' incubation, the isolatedpreparations were placed under registration, perfused with a salinesolution and oxygenated. Spontaneous potentials appear which areassociated with CA3 pyramidal cells. Excitation is induced by theaddition of bicucullin (50 μM).

The compounds of the invention, at various concentrations, or baclofenare then added.

The baclofen or the compounds of the invention are perfused for periodsof 10 minutes. The excitation rate is calculated during the four minutespreceding the perfusion of baclofen or the compounds of the inventionand during the last four minutes of the perfusion of the products to bestudied.

The inhibition is expressed as percentage excitation in relation to theinitial rate, which permits the determination of an inhibitingconcentration 50 (IC₅₀).

The compounds of the invention have an IC₅₀ of from 5 to 20 μM; baclofenin this test has an IC₅₀ of approximately 50 μM.

EXAMPLE 44 Stimulation of the Synthesis of Cyclic AMP in the Brain

The compounds to be tested are administered intraperitoneally at a doseof 10 mg/kg to mice of the OF1/ IFFA Credo strain.

24 hours after the last injection, the animals are sacrificed byfreezing, the cAMP present in these cerebral structures is dosed byradioimmunology according to Amersham's method (specific bindingprotein). Some of the compounds of the invention appear to be capable ofgreatly increasing the cerebral synthesis of cyclic AMP.

EXAMPLE 45 PHARMACEUTICAL COMPOSITION: TABLETS

Tablets each containing 1.5 mg of 3-(2-imidazolyl)-4-aminobutanoic acid

Formula for 1000 tablets:

    ______________________________________                                        3-(2-imidazolyl)-4-aminobutanoic acid                                                                1.5 g                                                  wheat starch           15 g                                                   cornstarch             15 g                                                   lactose                90 g                                                   magnesium stearate      2 g                                                   silica                  1 g                                                   hydroxypropylcellulose  2 g                                                   ______________________________________                                    

We claim:
 1. A compound selected from those of formula (I): ##STR18## inwhich: R₁ represents hydroxy, amino, lower alkylamino, lower alkoxy, orhalogen,R₂ represents hydrogen, lower alkyl, lower acyl, or loweralkoxycarbonyl, R represents: an aromatic radical selected fromunsubstituted and substituted quinoline, isoquinoline, and quinazoline,which the term "substituted" meaning that the group so qualified is besubstituted by one or more groups selected from halogen, lower alkyl,lower alkoxy, hydroxy, trifluoromethyl, nitro, amino, and loweralkylamino, its optical isomers and its salts of addition with apharmaceutically-acceptable base or acid, the terms "lower alkyl","lower alkoxycarbonyl", "lower alkoxy", "lower alkylamino" and "loweracyl" indicating group containing 1 to 6 carbon atoms inclusive in astraight or branched chain.
 2. A compound of claim 1 wherein R is aradical selected from the group consisting of unsubstituted quinoline,isoquinoline, and quinazoline radicals.
 3. A compound of claim 1,wherein R is a quinoline radical.
 4. A pharmaceutical composition usefulin treating a disorder related to a dysfunction of GABA_(B) receptorsincluding spastic disorders and senescence disorders, containing asactive principle an effective amount of a compound as claimed in claim 1in combination with a pharmaceutically-acceptable excipient or vehicle.5. A method for treating a living animal afflicted with a disorderrelated a dysfunction of GABA_(B) receptors, including spastic disordersor senescence disorders, comprising the step of administering to thesaid living animal an amount of a compound of claim 1 which is effectivefor alleviation of the said condition.